Horses experiencing exercise-induced pulmonary hemorrhage (EIPH), also known as “bleeding,” represent a serious problem to the horse racing industry. Bleeding is a condition in which the tiny blood vessels in a horse's lungs rupture due to stress sustained during intense physical exertion. Studies of horses in training and those in competition at racetracks have shown that from about 70% to 100% of them experience EIPH after performing. This has been shown both endoscopically (Pascoe et al. 1981; Sweeney, 1991) and from trans-tracheal washings (Whitwell and Greet, 1984). EIPH occurs in three variations. First, there is simple EIPH which is an acute condition resulting from the strain of exercise. Second, there is patent pulmonary hemorrhage (hereinafter “PPH”), which involves bleeding in the lungs as a reaction to an allergen, infection, or due to hypertension. Third, equine specimens experience composite bleeding, which is the result of the combined effects of simple EIPH and PPH.
Although numerous hypotheses have been proffered, it is generally accepted by the scientific community that simple EIPH occurs as the natural consequence of strenuous running due to the layout of the horse's organs and the way the equine body moves during high-speed galloping. The front half of a horse contains the heart, lungs and other major organs while the posterior half contains the intestines, which are suspended within the abdomen by ligaments. The rationale is based on studies by M. Manohar (Am J. Vet. Res, 1993, 54:142-146) and West et al. (J. Appl. Physiol., 1991, 71:573-582 and J. Appl. Physiol 1993, 75: 1097-1109) among others who have demonstrated that excessive pulmonary artery pressure and stress failure at the pulmonary capillary level is due to increased transmural pressure during strenuous exercise of the equine. Due to the back-and-forth motion of galloping, the horse's intestines swing like a pendulum at the end of the ligaments. When running at full speed, especially in the fastest sprint races, the movement of the intestines can get out of phase with the movement of the diaphragm in such a way that the intestinal mass is swinging forward as the horse is trying to exhale. This causes the diaphragm to be slammed forward and slightly upward. The diaphragm, in turn, squeezes part of the lung against the chest wall.
The lungs are filled with alveoli, tiny air sacs, and capillaries, miniscule blood vessels. The alveoli and capillaries are so fine and so interconnected that oxygen from the inhaled air can pass into the bloodstream, and carbon dioxide in the blood can pass out of the blood into the lungs to be exhaled. The capillaries are at their smallest and most efficient near the rear, tapered end of the lungs where they are in close proximity to the diaphragm. These extremely fine capillaries are repeatedly impacted by the forward-surging intestinal mass. As they rupture under the stress, the horse's air passages become clogged with blood. This causes difficulty in breathing which causes reduced athletic performance and/or a shortened athletic career. Thus, EIPH is one of the most serious veterinary problems facing the horse racing industry.
EIPH is defined as bleeding from the lungs as a consequence of exertion. Most horses involved in competitive racing experience EIPH. The incidence of EIPH ranges from about 30% for standardbreds and polo ponies to greater than 60% for Thoroughbreds, Quarterhorses, Appaloosas and Arabians. The minimum level of exertion needed to induce EIPH is unknown. Though it has been observed in some Thoroughbred horses after trotting, cantering and slow training gallops, EIPH is generally associated with more strenuous exertion, such as competitive flat racing, pacing, trotting, jumping or barrel racing. Moreover, EIPH is most prevalent in Thoroughbreds.
The present invention provides methods of treating or preventing a respiratory condition in a subject suffering from or susceptible to the respiratory condition by administering at least one infusion of a composition, comprising platelet enriched plasma, including platelet-rich plasma and/or platelet poor plasma, to the lungs, for example, directly to the lungs, of the subject, thereby treating or preventing said respiratory condition. In various embodiments, the condition is selected from the group consisting of simple exercise-induced pulmonary hemorrhage (EIPH), patent pulmonary hemorrhage and a combination thereof. In a particular embodiment, the respiratory condition is simple exercise-induced pulmonary hemorrhage (EIPH) occurring in the lungs or the arteries. In other embodiments, the condition is selected from the group consisting of asthma, lung cancer, cystic fibrosis, smoke inhalation, emphysema, bronchitis, chronic obstructive pulmonary disease (COPD) and sinusitis. In a particular embodiment, the platelet enriched plasma includes platelet rich plasma (PRP). In another embodiment, the platelet enriched plasma includes platelet poor plasma (PPP). In certain embodiments, the platelet enriched plasma includes a combination of each of platelet rich plasma and platelet poor plasma.
In various embodiments, at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 15 or 20 infusions of the composition are administered to the subject.
In certain embodiments, the subject is a human or an animal. In a particular embodiment, the subject is an equine, such as a stallion, mare, philly or gelding.
In various embodiments, the platelet enriched plasma may be fresh frozen plasma (FFP), autologously derived, homologously derived, or a combination thereof. Alternatively or in combination, the platelet enriched plasma comprises at least about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15% or 20% platelets. In certain embodiments, the platelet enriched plasma has a platelet concentration greater than about 200,000 platelets/μL, 300,000 platelets/μL, 400,000 platelets/μL, 500,000 platelets/μL, 600,000 platelets/μL, 700,000 platelets/μL, 800,000 platelets/μL, 900,000 platelets/μL, 1,000,000 platelets/μL, 1,100,000 platelets/μL, 1,200,000 platelets/μL, 1,300,000 platelets/μL, 1,400,000 platelets/μL, 1,500,000 platelets/μL, 1,600,000 platelets/μL, 1,700,000 platelets/μL, 1,800,000 platelets/μL, 900,000 platelets/μL, or 2,000,000 platelets/μL. For example, the platelet enriched plasma has a platelet concentration of greater than about 1 million platelets/μL.
In other embodiments, the composition comprises at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 125, 150, 175 or 200 mL of platelet enriched plasma.
The administration of platelet enriched plasma may enhance platelet concentration in the subject by at least 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 times. Alternatively or in addition, the administration of platelet enriched plasma enhances concentration of at least one growth factor in the subject by at least 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 times. For example, the at least one growth factor is selected from the group consisting of transforming growth factor beta (TGFbeta), vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), epidermal growth factor (EGF) and epithelial growth factor (EDF).
In one embodiment, the composition is administered directly to at least one lung. In an alternative embodiment, the composition is administered directly to the respiratory system upstream of the lungs and is subsequently transmitted to the lungs. For example, the composition may be administered directly to the bronthia, nasal cavity, sinuses, mouth, larynx, trachea or carina. In a particular embodiment, the composition is administered into at least one lung by direct administration to the carina, whereby the composition is subsequently transmitted to the main bronchi of at least one lung of the subject.
In certain embodiments, the composition is administered to the subject through an endoscopic biopsy channel, by use of a nebulizer, or through a syringe.
In various embodiments, the methods includes administering to the subject at least one of a platelet trigger or a diuretic, for example, furosemide. For example, the platelet trigger or diuretic, for example, furosemide, is administered previously, subsequently, or substantially simultaneously to the administration of the platelet enriched plasma. In certain embodiments, the composition includes at least one of the platelet trigger or the diuretic, for example, furosemide. The administration of platelet enriched plasma and platelet trigger in these foregoing embodiments may result in the release of at least one growth factor by platelet alpha granules, for example, transforming growth factor beta (TGFbeta), vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), epidermal growth factor (EGF) and epithelial growth factor (EDF). In a particular embodiment, the growth factor is TGFbeta.
In a further aspect, the invention is directed to a kit including a composition of platelet enriched plasma and instructions for administering the composition to the lungs of the subject. The platelet enriched plasma may be either autologous or homologous. The platelet enriched plasma may include platelet rich plasma, platelet poor plasma, or a combination thereof.
In certain embodiments, the kit may further include a means for administering the platelet enriched plasma to at least one lung of the subject, for example, an endoscopic biopsy channel, a syringe or a nebulizer. In certain embodiments, the means for administering the platelet enriched plasma to at least one lung of the subject is a means for directly administering the platelet enriched plasma to the at least one lung of the subject. Alternatively, the means for administering the platelet enriched plasma to at least one lung of the subject is a means for directly administering the platelet enriched plasma to the respiratory system upstream of the lungs, which is subsequently transmitted to the lungs. For example, the platelet enriched plasma may be administered direct to the bronchia, nasal cavity, sinuses, mouth, larynx, trachea or carina.
In certain embodiments, the kit may further include a platelet trigger and/or a diuretic, for example, furosemide.
In a further aspect, the present invention is directed to a method of treating or preventing exercise induced pulmonary hemorrhage in an equine by administering to the lung of the equine, a composition including platelet enriched plasma, wherein the composition is infused at the level of the carina such that it is distributed to the main bronchi of at least one lung of the equine, thereby treating or preventing exercise induced pulmonary hemorrhage.
The present invention is further illustrated by the following detailed description.